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CN-121987799-A - Bionic drug system with synergistic adjustment of lactic acid metabolism and application of bionic drug system in combination with PD-L1

CN121987799ACN 121987799 ACN121987799 ACN 121987799ACN-121987799-A

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a bionic medicine system with a synergistic adjustment function on lactic acid metabolism and application of the bionic medicine system in combination with PD-L1. The invention firstly provides a bionic drug system with the function of synergistically regulating lactic acid metabolism, which comprises a drug combination and a carrier for regulating lactic acid metabolism. The drug system of the invention can inhibit the discharge of lactic acid in tumor cells and promote the consumption of accumulated lactic acid, improve the tumor subacidity immunosuppression microenvironment, and finally synergistically enhance the treatment effect of the PD-L1 inhibitor.

Inventors

  • HUANG JINGBIN
  • XIE DANDAN
  • WANG FENGLING
  • QIN MING
  • LAI WENJING
  • ZHOU QIANG
  • WANG KUI

Assignees

  • 中国人民解放军陆军军医大学第二附属医院

Dates

Publication Date
20260508
Application Date
20251210

Claims (10)

  1. 1. A bionic drug system with a synergistic effect of regulating lactic acid metabolism is characterized by comprising a drug combination for regulating lactic acid metabolism and a carrier, wherein the drug combination consists of a MCT1 selective inhibitor and lactic acid oxidase, and the carrier is a bionic liposome compounded with erythrocyte membrane proteins.
  2. 2. The biomimetic pharmaceutical system of claim 1, wherein the MCT1 selective inhibitor comprises AZD3965, AR-C155858, BAY-8002, or 7ACC2.
  3. 3. The biomimetic pharmaceutical system of claim 1, wherein the mass range of MCT1 selective inhibitor and lactate oxidase in the pharmaceutical combination is 1:1-5:1.
  4. 4. The biomimetic pharmaceutical system of claim 1, wherein the mass ratio of erythrocyte membrane proteins in the biomimetic liposome is 0.5% -2%.
  5. 5. A combination for the treatment of solid tumors, comprising a biomimetic pharmaceutical system according to any one of claims 1-4 and a PD-L1 inhibitor with synergistic regulation of lactic acid metabolism.
  6. 6. The combination of claim 5, wherein the PD-L1 inhibitor comprises an anti-PD-L1 antibody.
  7. 7. The combination of claim 5, wherein the mass ratio of the biomimetic drug system with synergistic lactic acid metabolism modulating effect to the PD-L1 inhibitor comprises 1:1 to 2:1.
  8. 8. The combination of claim 5, wherein the solid tumor comprises breast cancer.
  9. 9. The application of a bionic drug system with a synergistic effect of regulating lactic acid metabolism in preparing an efficacy enhancer of a PD-L1 inhibitor is characterized in that the bionic drug system comprises a drug combination for regulating lactic acid metabolism and a carrier, wherein the drug combination consists of a MCT1 selective inhibitor and lactic acid oxidase, and the carrier is a bionic liposome compounded with erythrocyte membrane proteins.
  10. 10. The use according to claim 9, wherein the biomimetic drug system with synergistic regulation of lactic acid metabolism is used to enhance the inhibition of solid tumors by the PD-L1 inhibitor.

Description

Bionic drug system with synergistic adjustment of lactic acid metabolism and application of bionic drug system in combination with PD-L1 Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to a bionic medicine system with a synergistic adjustment function on lactic acid metabolism and application of the bionic medicine system in combination with PD-L1. Background Breast cancer is the first place in the incidence rate of all cancers of women in China, wherein Triple Negative Breast Cancer (TNBC) is used for clinical stage later, and has the characteristics of high malignancy degree, strong invasiveness, early metastasis, easy recurrence, poor prognosis and the like, and is the key point and the difficult point of breast cancer treatment. Recent researches show that the PD-1/PD-L1 antibody can exert the treatment effect on the advanced triple negative breast cancer only by combining with basic chemotherapy, but the effective rate of the PD-1/PD-L1 inhibitor on tumor treatment is less than half, which is in great relation with tumor microenvironment immunosuppression. Tumor cells are more prone to glycolytic energy even under aerobic conditions, lactic acid is the primary metabolite of glycolysis, accumulating excessively in the tumor microenvironment, causing most solid tumor tissues to be weakly acidic, inducing an acidic tumor microenvironment and leading to immunosuppression. TNBC is a solid tumor, and energy supply through glycolysis pathway leads to lactic acid accumulation in tumor tissue exocytosis, leading to limited therapeutic effect of PD-1/PD-L1 inhibitors. Monocarboxylic acid transporter 1 (MCT 1) is a member of the monocarboxylic acid transport family and plays an important role in tumor pH regulation and energy metabolism. AZD3965 is a MCT1 selective inhibitor, and researches show that AZD3965 can effectively inhibit lactic acid transport in tumors, increase the concentration of lactic acid in tumor cells, and further inhibit the growth of tumor cells. However, it was found clinically that intracellular free AZD3965 produces various side effects. Literature In Vitro and In Vivo Efficacy of AZD3965 and Alpha-Cyano-4-Hydroxycinnamic Acid in the Murine 4T1 Breast Tumor Model found that treatment with AZD3965 alone reduced the expression of the tumor proliferation marker Ki67, but increased the intracellular lactate concentration in the tumor. It was further found that accumulation of intracellular lactate may induce an up-regulation of MCT4 expression, which may adversely affect the sensitivity of MCT1 inhibition. There is therefore a need to propose new method strategies to alleviate the deficiencies of the prior art. Disclosure of Invention The invention aims to provide a bionic drug system with a synergistic lactic acid metabolism regulation function and application of a combined PD-L1 inhibitor in the field of tumor treatment, and the invention partially solves or alleviates the defects in the prior art. In a first aspect, the present invention provides a novel pharmaceutical system having a function of regulating lactic acid metabolism. A bionic drug system with a synergistic effect of regulating lactic acid metabolism comprises a drug combination for regulating lactic acid metabolism and a carrier, wherein the drug combination consists of a selective inhibitor of MCT1 and lactic acid oxidase, and the carrier is a bionic liposome compounded with erythrocyte membrane proteins. Further, the drug combination that modulates lactate metabolism and the carrier form a nano-like complex. Further, the MCT1 selective inhibitor includes AZD3965, AR-C155858, BAY-8002, or 7ACC2. Further, the mass ratio of the MCT1 selective inhibitor to the lactate oxidase in the pharmaceutical composition is in the range of 1:1-5:1. Preferably, the mass ratio of MCT1 selective inhibitor to lactate oxidase in the pharmaceutical combination is 5:1. Furthermore, the mass ratio of erythrocyte membrane proteins in the bionic liposome is 0.5% -2%. Preferably, the mass ratio of erythrocyte membrane protein in the bionic liposome is 2%. In another aspect of the invention, a novel pharmaceutical combination for treating tumors is provided. A combination for treating solid tumors comprises the bionic drug system with the synergistic effect of regulating lactic acid metabolism and a PD-L1 inhibitor. Preferably, the PD-L1 inhibitor is an anti-PD-L1 antibody. Further, the mass ratio of the bionic drug system with the function of synergistically regulating lactic acid metabolism to the PD-L1 inhibitor is 1:1-2:1. As a preferred aspect, the mass ratio of the bionic drug system with synergistic regulation of lactic acid metabolism to the PD-L1 inhibitor is 2:1. In a specific embodiment of the invention, AZD3965 is 2mg/kg and the PD-L1 inhibitor is 1mg/kg, but not limited thereto. Further, the solid tumors include, but are not limited to, breast cancer. Another aspect of the pres